By way of background, gamma-aminobutyric acid (GABA) and glutamic acid are major neurotransmitters which are involved in the regulation of brain neuronal activity. GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. Meythaler et al., Arch. Phys. Med. Rehabil. 1999; 80: 13-9. Imbalances in the levels of GABA in the central nervous system can lead to conditions such as spastic disorders, convulsions, and epileptic seizures. As described in U.S. Pat. No. 5,710,304, when GABA levels rise in the brain during convulsions, seizures terminate.
GABA is present in an estimated 60 to 70% of all the synapses in the brain (Med. Sci. Bull. 1997; 20(5)). There are two types of receptors, GABA-A and GABA-B. The B receptors appear to be involved in spasticity (Meythaler 1996, Young 1981), while the A receptors appear to be involved in the control of epilepsy (Med. Sci. Bull. 1997; 20(5)). In fact, GABA-A antagonists cause convulsions in animal models (Med. Sci. Bull. 1997; 20(5)) as well as spasticity.
Because of the inhibitory activity of GABA and its effect on convulsive states and other motor dysfunctions, the administration of GABA to subjects to increase the GABA activity in the brain has been tried. Because it is difficult to develop and administer a GABA compound which is able to cross the blood brain barrier utilizing systemic administration of GABA compounds, different approaches have been undertaken including making GABA lipophilic by conversion to hydrophobic GABA amides or GABA esters, and by administering activators of L-glutamic acid decarboxylase (GAD) whose levels vary in parallel with increases or decreases of brain GABA concentration which have been reported to increase GABA levels.
U.S. Pat. No. 4,094,992 to Kaplan et al. discloses benzylidene derivatives which are useful in the treatment of epilepsy and U.S. Pat. No. 4,361,583 to Kaplan discloses the use of the benzylidene derivatives for use in the treatment of pain. This class of drugs are strong GABA agonists which are effective on both GABA-B and GABA-A receptors.
One specific benzylidene derivative disclosed in U.S. Pat. No. 4,094,992 has the chemical structure 4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)methylene]amino]butanamide and is more commonly known as PROGABIDE (SL 76002). PROGABIDE does not appear to cause motor weakness in therapeutic dosages to control spasticity and does not appear to significantly affect cognition. There is some suggestion that progabide is an anti-epileptic agent and that it is also neuroprotective. Polasek et al., Epilepsy Research 1996; 25:177-84; Kulinskii et al., Eksperimntalnaia I Klinicheskaia Farmakologiia 1997; 60:56-8.
As discussed above, there are inherent difficulties in the effective administration of GABA and/or its derivatives to a subject in order to increase brain GABA levels. One of the most pronounced drawbacks of GABA administration is that it does not easily cross the blood brain barrier and, accordingly, does not enter the central nervous system after oral or parenteral administration. The benzylidene derivatives disclosed in the Kaplan et al. patent are considered to be “GABA-mimetic” and are capable of penetrating directly into the brain when administered by oral, endo-rectal, or parenteral routes.
It has been found, however, that, in the brain, when GABA agonists are delivered orally, they may cause some supraspinal activity which may contribute to clinical side effects. For example, for the GABA-B agonist baclofen, it has been found that following oral delivery of the drug that many patients experience central nervous system side effects such as drowsiness, confusion, or memory or attentional problems at the dosages required to reduce spasticity. Young et al., New Eng. J. Med., 1981; 304:28-33; Young et al., New Eng. J. Med., 1981; 304:96-99; Lazorthes et al., J. Neurosurg. 1990; 72:393-402; Sandy et al., Clin. Neuropharm. 1985; 8:294-295. Other central nervous system side effects of GABA agonists have included hallucinations, ataxia and memory impairments. Sandy et al., Clin. Neuropharm. 1985; 8:294-295; Hattab, Spasticity, Disordered Motor Control, 1980; Roy et al., Paraplegia 1986; 24:318-321. Additionally, the sudden withdrawal of orally delivered GABA compounds may itself lead to seizures and hallucinations. Terrence et al., Arch. Neurol. 1981; 38:588-589.
The side effects noted above with the systemic administration of GABA agonists can be largely averted by utilizing intrathecal drug delivery since intrathecal delivery of GABA compounds to the lumbar or mid-thoracic spinal intrathecal space concentrates the medication in the lower area of the spinal cord cerebrospinal fluid at much higher levels than those attainable via the oral route of administration (Meythaler, McCary, Hadley 1996). Typically, the type of delivery system for intrathecal therapy consists of a subcutaneously placed pump having a reservoir which is attached to an intraspinal catheter. This drug delivery methodology concentrates the medication within the spinal subarachnoid space and the thoracolumbar and sacral spinal regions at a much higher level than that attainable via the oral route of administration. Meythaler et al., J. NeuroSurgery 1997; 87:415-9. From the subarachnoid space, the cerebrospinal fluid then flows to the arachnoid villi for reabsorption thereby avoiding a significant part of the cerebral hemispheres. Meythaler et al., Arch. Phys. Med. Rehabil. 1996; 77:461-466. Only low levels of the medication have the potential to reach the brainstem or cerebrum as studies have demonstrated the lumbar-to-cisternal drug cerebrospinal fluid (CSF) drug concentration gradient is 4.1:1. Kroin et al., Parenteral Drug Therapy in Spasticity and Parkinsons Disease 1991, pp. 73-83. By utilizing intrathecal drug delivery, the cognitive side effects of oral drug delivery, such as drowsiness and lethargy, can be avoided. Coffey et al., J. Neurosurg. 1993; 78:226-232; Penn et al., N. Engl. J. Med. 1989; 320:1517-1522; Knuttson et al., J. Neurol. Sci. 1974; 23:473-484. Furthermore, intraventricular delivery does the same for the periventricular area or region of the brain.
Preclinical animal studies in a canine model of the GABA-B agonist, baclofen (2000 μg/d for 28 days), intrathecally through a subcutaneously implanted pump demonstrated no deleterious histopathology in the studied animals. (Sabbe 1993). Initial work examining the use of GABA agonists both by systemic delivery and by intrathecal delivery in animal models revealed that baclofen produced a dose dependent analgesia (Bergmann; Clin. Neuropharcol. 1985; 8:13-26; Wilson et al., European J. Pharmacol. 1978; 51:323-330) and a reduction in motor tone in normal (Bergmann; Clin. Neuropharcol. 1985; 8:13-26; Wilson et al., European J. Pharmacol. 1978; 51:323-330; Kroin et al., Exp. Brain Research 1984; 54:191-194) and genetically spastic animals (Klockgether et al., Neurosci. Lett. 1989; 97:221-226).
Based on electrophysiology and the above-discussed preclinical studies, the mechanism of the anti-spasticity associated with intrathecally delivered baclofen is believed to be due to the hyperpolarization of motor horn cells. After the development or onset of upper motor neuron lesions, a variety of long term changes are observed in the brain. Mendell, Physiological Reviews 1984; 64(1):260-324. Among these changes, there is an increase in Ia motor unit activity. Wilson et al., European J. Pharmacol. 1978; 51:323-330. In humans, while motor horn cells show little change in recurrent inhibition after spinal injury, there is a loss of regulation of Renshaw cell inhibition (Katz et al., Brain 1982 March, 105(Pt 1): 103-24) and an increased motor neuron excitability (Shemesh et al., Paraplegia 1977 Nov., 15(3):238-44).
Despite the initial success of the intrathecally delivered GABA agonist baclofen in treating the dystonia/spasticity associated with spinal disorders (Meythaler et al., Arch. Phys. Med. Rehabil. 1999; 80:13-9; Penn et al., N. Engl. J. Med. 1989; 320:1517-1522; Muller et al., Local-spinal therapy of spasticity 1988, pp. 223-226), there is still little interest in treating cerebral disorders with intrathecally administered GABA agonists. This lack of interest appears to stem from the lack of success with oral medications in the treatment of dystonia/spasticity resulting from traumatic brain injury (Katz, Phys. Med. Clin. N. Am. 1992; 3:319-335; Mann, J. Neuro. Rehab. 1991; 5:51-54; Katz, Am. J. Phys. Med. Rehabil. 1988; 67:108-116). However, there were indications from some reports that this may be a useful methodology to improve the functional outcome of traumatically brain injured patients. Meythaler et al., J. NeuroSurgery 1997; 87:415-9; Meythaler et al., Arch. Phys. Med. Rehabil. 1996; 77:461-466. Once clinical trials utilizing programmable infusion pump systems to intrathecally deliver baclofen for the management of dystonia/spasticity in traumatic brain injury were finally initiated, the results were favorable. Meythaler et al., J. NeuroSurgery 1997; 87:415-9; Akman et al., Paraplegia 1993; 31:516-20. However, not all patients have had a significant sustained response with intrathecally administered baclofen (Meythaler et al., Arch. Phys. Med. Rehabil. 1999; 80:13-9), which may be related to its effect only on GABA-B receptors.
Gamma-aminobutyramide appears to bind to both GABA-A and B receptors and it is an excellent candidate for use intrathecally as it is soluble in water and relatively stable for long periods of time. It is able to penetrate from the CNS into the central nervous system. Both the temporal horns and the frontal lobes of the brain are contiguous to the cerebral ventricles which contain CSF. 70% of all seizures are found to be originating in these areas by EEG monitoring. Consequently, intraventricular delivery of gamma-aminobutyramide should be useful in alleviating seizures.
Accordingly, the use of gamma-aminobutyramide, a solubility product of PROGABIDE, which is an agonist of both GABA-B receptors and GABA-A receptors, for the treatment of dystonia/spasticity in traumatically brain injured individuals is likely to have a more significant effect. This outcome is indicated by research which indicates that systemically delivered diazepam, a GABA-A receptor agonist, also has profound effects on dystonia and spasticity. Meythaler et al., Perspectives in Neurosurg. 1996; 7(2):99-107. The intrathecal and/or intraventricular administration of gamma-aminobutyramide directly into the cerebrospinal fluid will significantly limit its systemic toxicity due to the low doses delivered and to the small amount of the chemical or its metabolites that will reach the liver from that reabsorbed from the reabsorbed CSF at the arachnoid villi. Additionally, it has been speculated that gamma-aminobutyramide could be useful to reduce spasticity, dystonia, and have effects as an anti-convulsant if its toxicity and delivery issues could be solved. Kaplan et al., J. Med. Chem., 1980; 23:702-4. Finally, GABA agonists have been used for the treatment of neurogenic pain (Baclonja M, et al., Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA, 1998, 280.1831-6). GABA-B agonists given intrathecally may also aid in the treatment of vaso-motor disorders related to upper motor neuron injury or illness (Rode G., et al., Regression of vasomotor disorders under intrathecal baclofen in a base report. Spinal Cord, 1999; 37:370-2).
There is some evidence that the movement disorder tardive dyskinesia may respond to GABA agonists. It is felt that the receptors that are targeted are GABA receptors near the globus pallidus and corpus callosum (Soares et al., Cochran Library, Issue 1 1999). Both of these areas are contiguous to the flow of the CSF from the lateral ventricles and down through the third ventricle. While GABA agonists may have been somewhat effective, there were considerable side effects with systemic delivery that, again, can be averted via intraventricular delivery. Accordingly, it would be desirable and advantageous to treat traumatic brain injuries and/or pain with GABA agonists without the side-effects and disadvantages described above. Furthermore, combining either intrathecal or intraventricular administration of gamma-aminobutyramide, derivatives thereof, and/or a drug or compound which yields gamma-aminobutyramide as an intermediate, metabolite or a by-product, with an implantable pump to provide constant delivery of the drug will provide anti-spasticity, anti-convulsive, and anti-epileptic efficacy.